Gynecologic cancer remains a major health problem for women in this country, with approximately 25,000 deaths annually attributed to this problem. Unfortunately, most of these tumors remain untreatable when diagnosed in the advanced stage. The purpose of this project is to characterize the molecular genetics of this group of tumors and ultimately use that information for clinical application in rationally designing therapeutic, early detection, and prevention trials. We have characterized endometrial and ovarian specimens which span the histologic spectrum from benign to malignant for mutations in the ras, p53 and Rb genes. For endometrial cancers, we have analyzed curettage specimens. Activated ras genes are found in the atypical hyperplasias (14%) and endometrial carcinomas (5%); p53 mutations are found in approximately 15% of atypical hyperplasia and carcinomas. These studies will help to identify the molecular genetic events that are important in the genesis of endometrial cancer and their use for the its early detection. Evaluation of ovary tumors revealed that activated ras genes are found in benign (10%) and "LMP" tumors (30%) while ovarian carcinomas (5- 10%) do not. In addition, mutations in the tumor suppressor genes p53 and Rb occur in ovarian carcinomas (48 and 14% respectively) but are not present in LMP tumors. This suggested that these tumors are discrete biologic entities. We are now extending these results by examining 143 specimens of advanced ovarian cancer from a large prospective trial (GOG#111) for mutations in the p53 gene and overexpression of HER2/neu. Future projects will examine the value of p53 mutations as a prognostic or an early detection marker in ovarian cancers by examining large numbers of early stage ovarian cancers. This will involve characterizing early ovarian cancers from GOG#95 for the expression of HER2/neu, p53 and EGFR. Finally, to identify potential new markers of ovarian cancer and genes important in its pathogenesis, malignant ovarian epithelium is being compared to its benign counterpart using differential display technology. Genes which are differentially expressed will be isolated, cloned and characterized for their role in the development of ovarian cancer.